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Adaptive Gene Regulation in the Striatum of RGS9-Deficient Mice
Please always quote using this URN: urn:nbn:de:bvb:20-opus-117048
- Background: RGS9-deficient mice show drug-induced dyskinesia but normal locomotor activity under unchallenged conditions. Results: Genes related to Ca2+ signaling and their functions were regulated in RGS9-deficient mice. Conclusion: Changes in Ca2+ signaling that compensate for RGS9 loss-of-function can explain the normal locomotor activity in RGS9-deficient mice under unchallenged conditions. Significance: Identified signaling components may represent novel targets in antidyskinetic therapy. The long splice variant of the regulator ofBackground: RGS9-deficient mice show drug-induced dyskinesia but normal locomotor activity under unchallenged conditions. Results: Genes related to Ca2+ signaling and their functions were regulated in RGS9-deficient mice. Conclusion: Changes in Ca2+ signaling that compensate for RGS9 loss-of-function can explain the normal locomotor activity in RGS9-deficient mice under unchallenged conditions. Significance: Identified signaling components may represent novel targets in antidyskinetic therapy. The long splice variant of the regulator of G-protein signaling 9 (RGS9-2) is enriched in striatal medium spiny neurons and dampens dopamine D2 receptor signaling. Lack of RGS9-2 can promote while its overexpression prevents drug-induced dyskinesia. Other animal models of drug-induced dyskinesia rather pointed towards overactivity of dopamine receptor-mediated signaling. To evaluate changes in signaling pathways mRNA expression levels were determined and compared in wild-type and RGS9-deficient mice. Unexpectedly, expression levels of dopamine receptors were unchanged in RGS9-deficient mice, while several genes related to Ca2+ signaling and long-term depression were differentially expressed when compared to wild type animals. Detailed investigations at the protein level revealed hyperphosphorylation of DARPP32 at Thr34 and of ERK1/2 in striata of RGS9-deficient mice. Whole cell patch clamp recordings showed that spontaneous synaptic events are increased (frequency and size) in RGS9-deficient mice while long-term depression is reduced in acute brain slices. These changes are compatible with a Ca2+-induced potentiation of dopamine receptor signaling which may contribute to the drug-induced dyskinesia in RGS9-deficient mice.…
Author: | Kathy Busse, Rainer Strotmann, Karl Strecker, Florian Wegner, Vasudharani Devanathan, Antje Gohla, Torsten Schöneberg, Johannes Schwarz |
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URN: | urn:nbn:de:bvb:20-opus-117048 |
Document Type: | Journal article |
Faculties: | Fakultät für Biologie / Rudolf-Virchow-Zentrum |
Language: | English |
Parent Title (English): | PLOS ONE |
Year of Completion: | 2014 |
Volume: | 9 |
Issue: | 3 |
Pagenumber: | e92605 |
Source: | PLoS ONE 9(3): e92605. doi:10.1371/journal.pone.0092605 |
DOI: | https://doi.org/10.1371/journal.pone.0092605 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/24663062 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | L-3,4-Dihydroxyphenylalanine-induced dyskinesia; Parkinsons disease; adenylyl cyclase; ampa receptors; cholinergic interneurons; dopa-induced dyskinesia; endocannabinoid release; long-term depression; medium spiny neurons; synaptic plasticity |
Release Date: | 2015/08/14 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung |